Cigarette smoking represents the most commonly used drug of abuse in American society. Despite extensive public education campaigns regarding the deleterious consequences of smoking, the proportion of women who smoke in North America has been estimated to be between 18-28%. In addition to active smoking, one-third to one-half of pregnant women are exposed to passive smoke. Identification of nicotine and its metabolite cotinine in hair samples of neonates indicates that human fetuses are exposed to significant levels of nicotine both through active smoking by their mothers and through maternal exposure to passive smoke. Among other abnormalities, an increased incidence of Attention Deficit Disorders and sudden infant death syndrome (SIDS) occurs in the offspring of maternal smokers. The purpose of this proposal is to evaluate the post-natal consequences of prenatal nicotine exposure in a rodent model, with particular emphasis on the development of sleep-wake and circadian systems. An underlying hypotheses of our work is that impaired or delayed maturation of the circadian and sleep/wake systems plays a role in the occurrence of SIDS. We have found that prenatal nicotine exposure in rat pups induces expression of the immediate early gene (IEG) c-fos in the fetal, but not the maternal, suprachiasmatic nucleus (SCN). Since induction of c-fos mRNA in the adult SCN by light exposure has been associated with phase-shifts of the circadian system, our results suggest that nicotine exposure may induce a desynchrony between the circadian timekeeping system of the mother and the fetus. To test this hypothesis and to further elucidate the signal transduction pathway in the SCN, we will determine the molecular basis for the differential response of the fetal vs. maternal SCN to prenatal nicotine exposure. We hypothesize that this differential response may be due to differential composition of the nicotinic cholinergic receptor in the fetal and adult SCN. To further understand the signal transduction pathway underlying nicotine-induced c- fos expression in the fetal SCN, we will determine whether prenatal nicotine exposure causes phosphorylation of the CREB and/or SRF proteins in the fetal SCN and identify other IEGs induced in the fetal SCN by prenatal nicotine exposure.